Sex-Specific Control of Fat Mass and Counterregulation by Hypothalamic Glucokinase

Steinbusch, Laura K. M.; Picard, Alexandre; Bonnet, M; Basco, Davide; Labouèbe, Gwenaël; Thorens, Bernard

doi:10.2337/db15-1514

Cited by 23 publications

(32 citation statements)

References 49 publications

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“…We used female mice in our streptozotocin studies to maximize efficient use of the I366F breeding colony. Gender differences in counter-regulation have been reported in human and murine studies [40] , [44] . It is thus possible that background strain and/or gender might have altered our findings.…”

Section: Discussionmentioning

confidence: 93%

“…A previous study used short hairpin RNA-knockdown of VMN GCK in rats, reporting increased epinephrine responses to non-clamped (insulin-bolus induced) hypoglycemia [39] . It is possible that VMN neurons involved in GCK-mediated counter-regulation will be non-SF1 cells given that genetic inactivation of GCK specifically within VMN SF1 cells does not increase epinephrine or glucagon release in response to hypoglycemia [40] .…”

Section: Discussionmentioning

confidence: 99%

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Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes

Chakera

Hurst

Spyer

et al. 2018

Molecular Metabolism

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ObjectiveAppropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic β-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses.MethodsHyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase.ResultsGCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated β-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in β-cells. For epinephrine, we found increased responses in GCK-MODY patients, in β-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release.ConclusionsOur data suggest that glucokinase in brain and other non β-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes

Chakera

Hurst

Spyer

et al. 2018

Molecular Metabolism

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“…To generate mice with inactivation of the Gck gene in α-cells ( αGckKO mice), we crossed Gck lox/lox mice 9 with preproglucagon-Cre ( Gcg-Cre ) mice 15 . These mice were further crossed with Rosa26-tdtomato mice and ~70% of the glucagon-positive cells also expressed tdtomato (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The resulting increase in intracellular Ca 2+ leads to glucagon secretory granules exocytosis. Extrinsic factors also play an important role in triggering glucagon secretion, in particular, the signals from the sympathetic and parasympathetic branches of the autonomic nervous system 4 , 5 , which are activated by hypoglycemia-sensing neurons present in the extrapancreatic sites, such as the hepatoportal vein area 6 , 7 and the central nervous system 5 , 8 , 9 . On the other hand, suppression of glucagon secretion by hyperglycemia relies on paracrine regulation, including insulin-induced inhibition and/or somatostatin-induced inhibition of α-cells 10 .…”

Section: Introductionmentioning

confidence: 99%

α-cell glucokinase suppresses glucose-regulated glucagon secretion

et al. 2018

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Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that α-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck (αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of KATP channels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. αGckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an α-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype.

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“…Finally, developmental ablation of glucokinase ( Gck ), the major glucose‐sensing enzyme, in murine VMH neurones leads to sex differences in fat mass, glucagon secretion and autonomic nervous activity, with females showing increased gonadal, inguinal and total fat mass, decreased hypoglycemia‐induced glucagon secretion, and reduced parasympathetic and sympathetic nerve activity compared to males . These findings further suggest that VMH Gck is required for hypoglycemia counter‐regulation in females but not males . Ultimately, sex differences in the VMH contribute to the differential recruitment of circuitry underlying metabolic homeostasis.…”

Section: Sex‐specific Functions Regulated By the Vmhmentioning

confidence: 99%

Selective sexual differentiation of neurone populations may contribute to sex‐specific outputs of the ventromedial nucleus of the hypothalamus

Kammel

Correa

2019

J Neuroendocrinology

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| INTRODUC TI ONSex differences in the brain include molecular, cytoarchitectural or connectivity features of cells and brain regions that are non-neutral between males and females. These sex differences are embedded within neural circuits and could provide the functional basis for sex-typical behaviours and physiological responses ( Figure 1). 1,2The origins of these sex differences are not fully understood, although they can be the result of genetic, hormonal or environmental factors acting in adulthood or during development. 3 Some of the best studied sex differences in the brain appear to arise from the effects of sex hormones, mainly testosterone or its metabolite oestradiol. Activational effects of sex hormones arise in adulthood and are reversible. By contrast, organisational effects of sex hormones are programmed during a short perinatal time window, or critical period, and are permanent. For example, perinatal oestradiol can alter cellular survival and lead to sex differences in neurone number in the sexually dimorphic nucleus of the preoptic area of the hypothalamus and the anteroventral periventricular nucleus (AVPV) in rodents. 4-9 However, other hypothalamic regions exhibit sex differences in gene expression or morphology rather than cell number. In the VMHvl, perinatal oestradiol establishes permanent sex differences in gene expression. 4,5 This sexual differentiation of cellular phenotype extends to glial cells, including astrocytes 10 and microglia, 11 and opens the door to more subtle differences between male and female brains.Earlier reviews have highlighted some of the challenges in characterising sex differences in the brain: (i) sex differences Abstract Sex differences among neurones in the ventrolateral region of the ventromedial hypothalamic nucleus (VMHvl) allow for the display of a diversity of sex-typical behaviours and physiological responses, ranging from mating behaviour to metabolism.Here, we review recent studies that interrogate the relationship between sex-typical responses and changes in cellular phenotypes. We discuss technologies that increase the resolution of molecular profiling or targeting of cell populations, including singlecell transcriptional profiling and conditional viral genetic approaches to manipulate neurone survival or activity. Overall, emerging studies indicate that sex-typical functions of the VMH may be mediated by phenotypically distinct and sexually differentiated neurone populations within the VMHvl. Future studies in this and other brain regions could exploit cell-type-specific tools to reveal the cell populations and molecular mediators that modulate sex-typical responses. Furthermore, cell-type-specific analyses of the effects of sexually differentiating factors, including sex hormones, can test the hypothesis that distinct cell types within a single brain region vary with respect to sexual differentiation. K E Y W O R D Sneuroactive steroids, neuropeptides, oestrogens, progestogens, steroids

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Sex-Specific Control of Fat Mass and Counterregulation by Hypothalamic Glucokinase

Cited by 23 publications

References 49 publications

Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes

Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes

α-cell glucokinase suppresses glucose-regulated glucagon secretion

Selective sexual differentiation of neurone populations may contribute to sex‐specific outputs of the ventromedial nucleus of the hypothalamus

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